Aminobenzodiazepine compounds and methods



United States Patent Ofifice 3,374,225 AMINOBENZODIAZEPINE COMPOUNDS ANDMETHODS Earl Reeder, Nutley, Arthur Stempel, Teaneck, and Leo HenrykSternbach, Upper Montclair, N.J., assignors to Hofimann-La Roche Inc.,Nutley, N.J., a corporation of New Jersey No Drawing.Continuation-impart of application Ser. No. 240,750, Nov. 28, 1962. Thisapplication Mar. 28, 1963, Ser. No. 268,553

8 Claims. (Cl. 260-239) The instant application is acontinuation-in-part of our application Ser. No. 240,750, filed Nov. 28,1962, now Patent No. 3,340,253, and is also a continuation-in-part ofour application Ser.- No. 178,551, filed Mar. 9, 1962, and nowabandoned.

This invention relates to novel heterocyclic compounds and methods fortheir preparation. More particularly, the invention relates to2-amino-5-phenyl-3H-1,4-benzodiazepines bearing a hyroxy group orsubstituted hyroxy group in the 3-position. Thus, the novel compounds ofthis invention are selected from the group consisting of those of theformula GI-IORa I and their pharmaceutically acceptable salts, wherein Ris selected from the group consisting of hydrogen, lower alkanoyl, andar-lower alkanoyl; R is selected from the group consisting of hydrogenand lower alkyl; R is selected from the group consisting of hydrogen,lower alkyl, lower alkanoyl, aroyl and ar-lower alkanoyl; R is selectedfrom the group consisting of hydrogen, halogen, lower alk-oxy andtrifluoromethyl; and R is selected from the group consisting ofhydrogen, halogen, trifluoromethyl, 'nitro, lower alkylthio and loweralkyl.

The term lower alkyl includes both straight and branced chain groupssuch as methyl, ethyl, propyl, isopropyl, and the like. Similarly, theterm lower alkoxy refers to groups such as methoxy and the like. Theterm lower alkenyl refers to both straight and branched chainunsaturated hydrocarbon groups such as allyl and the like. The termlower alkanoyl refers to both straight and branched chain aliphaticcarboxylic acid groups such as acetyl, propionyl, butyryl, isovaleroyl,and the like. Similarly, the term aroyl" refers to groups such asbenzoyl and the like.

The compounds of Formula I above form pharmaceutically acceptable acidaddition salts with both inorganic and organic pharmaceuticallyacceptable acids, such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, aceticacid, succinic acid, maleic acid, methanesulfonic acid, ptoluene-sulfonic acid, and the like. Such acid addition salts are alsowithin the scope of the invention. p Compounds of Formula I above,wherein R is lower 3,374,225. Patented Mar. 19, 1968 alkanoyl, aroyl orar-lower alkanoyl can be prepared by reacting a compound of the formulawherein R R R and R have the same meanings as above, with an acidanhydride, diacyl sulfide or acid halide. Via this procedure, the4-position oxygen is split oh and the 3-position carbon atom isconcurrently acyloXyl-ated. The acid anhydride, diacyl sulfide or acidhalide (chlorides are preferred) used should, of course, be the onewhich would yield the desired lower alkanoyl, aroyl or ar-lower alkanoylgroup (R in Formula I above). Thus, if it is desired to prepare acompound wherein R is acetyl, either acetic anhydride, diacetyl sulfide,or acetyl chloride can be used as the acylating agent. Thus, theacylating agents are selected from the group of lower alkanoylanhydride, aroyl anhydride, ar-lower alkanoyl anhydride, di-loweralkanoyl sulfide, diaroyl sulfide, diar-lower alkanoyl sulfide, loweralkanoyl halide, aroyl halide and ar-lower alkanoyl halide. The reactionis conveniently either conducted in a conventional organic solvent suchas dimethylformamide, pyridine, or the like; or, in the case whereinacid anhydride or diacyl sulfide is used as the acylating agent, saidacid anhydride or diacyl sulfide can itself serve as the reactionmedium. The reaction is, if desired, conducted at room temperature, butcan be conducted at above or below room temperature.

' In those cases wherein R in Formula II is hydrogen, compounds ofFormula I above, wherein R and R are the same acyl group, can beobtained. On the other hand, starting material compounds of Formula IIabove, wherein R is already an acyl group can be reacted via the aboveprocdure to yield compounds wherein R remains unchanged and accordingly,R and R are the same or dissimilar acyl groups. Moreover, it has beenfound that by using dimethylformamide as the reaction medium, compoundsof Formula II, wherein R is hydrogen can be selectively acylated toyield compounds of Formula I wherein R is hydrogen. Also, aroylation hasbeen found to selectively occur at the 3-position and not to'affect the2-position nitrogen atom.

Compounds of Formula I above, wherein R is hydrogen, can be prepared byhydrolysis of compounds of Formula I above wherein R is lower alkanoyl,aroyl or ar-lower alkanoyl. Suitably the hydrolysis is effected inalkaline medium. The alkaline treatment is suitably effected at roomtemperature, though such is not critical and the hydrolysis can beconducted at higher or lower temperatures. However, of course, thetemperature should not be so high as to cause decomposition of thedesired end product. Said alkaline hydrolysis can suitably be effectedin an aqueous medium containing an organic solvent such as dioxane,tetrahydrofuran or like organic solvents miscible with water.

Compounds of Formula I wherein R is lower alkyl can be prepared fromcorresponding compounds of Formula I wherein R is other than loweralkyl. Suitably, such a compound of Formula I is reacted with a loweralkanol of the formula R OH, wherein R is lower alkyl, to yieldcorresponding compounds of Formula I wherein R is lower alkyl. Suitably,this reaction is elfected by treating an acid addition salt, forexample, a hydrohalide such as the hydrochloride, of a compound ofFormula I wherein R is hydrogen, lower alkanoyl, aroyl or ar-loweralkanoyl, with a lower alkanol. Alternatively, said compound of FormulaI in base form or in the form of an acid addition salt can be treatedwith lower alkanol in the presence of an acid such as a hydrohalic acid,for example, hydrochloric acid. The treatment with lower alkanol can beeffected using the lower alkanol itself as the solvent, or in thepresence of an inert organic solvent. Also, the treatment can beeifected in the presence or absence of water. The treatment can beelfected at room temperature or elevated temperatures, but the latterare preferred. Advantageously, the reaction with lower alkanol iseffected at reflux, for example, in the case of the lower molecularweight lower alkanols, between about 60 C. and about 80 C.

The compounds of Formula I above are useful as anticonvulsants. They areespecially useful by virtue of their substantial lack of unwanted sideelfects. Said compounds or their pharmaceutically acceptable acidaddition salts can be administered, with dosage adjusted to individualrequirements, in conventional pharmaceutical dosage forms. For example,they can be administered internally, i.e. parenterally or enterally, inthe form of tablets, suspensions, solutions, capsules, drages, and thelike.

The following examples are illustrative, but not limitative of theinvention. All temperatures are in degrees centigrade.

Example 1 A solution of 31 g. of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine 4-oxide in a mixture of 360 ml. of pyridineand 180 ml. of acetic anhydride was heated to 50 for 20 minutes, thenleft at room temperature for four days. The solution was concentrated invacuo to a small volume, and the residue was treated with ether andpetroleum ether, which caused the precipitation of crystals. The firstfraction of crystals (19.1 g.) consisted of almost pure 7-chloro 2(N-methylacetamido)-5- phenyl-BH-1,4-benzodiazepine 4-oxide. The secondfraction obtained after the addition of more petroleum ether weighed11.8 g. and melted below 140. After recrystallization of this fractionform ether or a mixture of methylene chloride, ether and petroleumether, 7-chloro-2-(N- methylacetamido) 3acetoxy-S-phenyl-BH-1,4-benzodiazepine was obtained. The product isdimorphic and forms colorless prisms melting at 145146 or at 159- 160.

Example 2 A solution of 10 g. of 7-chloro-2-(N-methylacetamido)-5-phenyl-3H-1,4-benzodiazepine 4-0xide in ml. of acetic anhydride washeated for 10 minutes to 80. The solution was concentrated in vacuo andthe residue recrystallized from a mixture of acetone and petroleumether. First 2.6 g. of unreacted starting material crystallized out andwas removed. Then more petroleum ether was added, yielding crystals of7-chloro-2-(N-methylacetamido)-3-acetoxy-5-phenyl 3H 1,4-benzodiazepine.The product was crystallized from ether or a mixture of methylenechloride, ether and petroleum ether. It is dimorphic and forms colorlessprisms melting at 145-146 or at 159-160".

Analysis.-Calcd, for C H N O Cl: C, 62.58; H, 4.73; O, 12.51; acetyl,22.43. Found: C, 62.56; H, 4.47; O, 12.91; acetyl, 22.81.

Example 3 To a solution of 64 g. of 7-cholor-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 600 ml, of

dimethylformide, 25.2 ml. of acetyl chloride was added with outsidecooling. Crystals of 7-chloro-2-methylamino-3-acet0xy-S-phenyl-3H-1,4-be-nzodiazepine hydrochloride started toprecipitate after a short time and were filtered off after about 1 hour.After recrystallization from a mixture of ethanol and petroleum etherthe product formed colorless needles melting at 2122l3.

Analysis.-Calcd. for C H N O Cl: C, 57.15; H, 4.53. Found: C, 56.99; H,4.80.

The above described 7-chloro-2-methylamino-3acetoxy-5-phenyl-3H-1,4-benzodiazepine hydrochloride was treated with anexcess of ice cold dilute sodium hydroxide, and the liberated base wasextracted with methylene chloride. The methylene chloride layer wasseparated, dried, and concentrated in vacuo and the residue wascrystallized from a mixture of methylene chloride and ether to yieldcolorless prisms of 7-chloro-2-methylamino-3-acetoxy-5-pheuyl-3H-1,4-benzodiazepine melting at 202-203".

Analysis.Calcd. for C H N O Cl: C, 63.25; H, 4.72; N, 12.30; acetyl,12.6. Found: C, 63.12; H, 4.77; N, 12.46, 12.47; acetyl, 12.94.

Example 4 A solution of 3.8 g. of7-chloro-2-(N-methylacetamido)-3-acetoxy-5-phenyl-3H-1,4-benzodiazepinein 50 ml. of dioxane was treated with 10 ml. of 1 N sodium hydroxide.After 1 /2 hours standing at room temperature, the mixture wasconcentrated in vacuo to a small volume and diluted with water andether. The ether layer was separated, dried, concentrated to a smallvolume, and the precipitated crystals were filtered oil. Thus, colorlessprisms were obtained which after recrystallization from acetone wereidentical with an original sample of 7-chloro-2-methylamino-3-acetoxy 5phenyl-3H-1,4-benzodiazepine.

Example 5 A solution of 1 g. of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-3-ol in a mixture of 10 ml. of pyridine and 5 ml.of acetic anhydride was left at room temperature for 16 hours,concentrated in vacuo to dryness and the residue recrystallized from amixture of acetone and petroleum ether yielding colorless prisms of 7-chloro-2-methylamino-3-acetoxy-5-phenyl-3H- 1,4 benzodiazepine.

Example 6 A solution of 3.4 g. of7-chloro-2-rnethylamino-3-acetoxy-5-phenyl-3H-1,4-benzodiazepine in amixture of 50 ml. of dioxane and 10 ml. of 1 N sodium hydroxide wasstirred at room temperature for 4 hours and then concentrated in vacuoto a small volume. Water was added and the reaction product wasextracted with methylene chloride. The organic layer was dried,concentrated in vacuo and the residual oil was crystallized from ether.After recrystallization from a mixture of methylene chloride andpetroleum, ether, colorless needles of 7-chloro-2-methylamino 5phenyl-3H-1,4-benzodiazepin-3-ol melting at 184-186 were obtained.

Analysis.Calcd. for C H ClN O: C, 64.11; H, 4.71; N, 14.02. Found: C,64.11; H, 4.98; N, 13.58.

Example 7 To a solution of 1.9 g. of7-chloro-2-(N-methylacetamido)-3-acetoxy-5-phenyl-3H-1,4-benzodiazepinein 50 ml. of dioxane was added 10 m1. of 1 N sodium hydroxide. Themixture was stirred at room temperature for 20 hours and thenconcentrated in vacuo. The residue was dissolved in methylene chloride,washed with water, the organic layer was separated, dried, andconcentrated in vacuo. The residue was crystallized from methylenechloride yielding colorless needles of 7-chloro-2-methylamino-5-phenyl-3-H-1,4-benzodiazepin-3-oL.

Example 8 To a solution of 12 g. of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml. of dimethylformamide wasadded 5.5 g. of propionyl chloride. The solution was coole-d, left atroom temperature for 1 hour and then diluted with ice water and dilutesodium hydroxide. The mixture was then extracted with methylenechloride, the organic layer washed with dilute hydrochloric acid andwater, dried and concentrated in vacuo. The residual oil wascrystallized from ether or from a mixture of ether and petroleum etheryielding colorless prisms of 3-propionyloxy-7-chloro 2 methylamino-S-phenyl-3H-1,4-benzodiazepine melting at 197-198".

Analysis.Calcd. for C H ClN O C, 64.12; H, 5.10; N, 11.81. Found: C,64.15; H, 5.38; N, 11.70, 11.71.

Example 9 of 3-butyryloxy-7-chloro-2-methylamino-5-phenyl-3H-1,-

4-benzodiazepine melting at 174-175 Example To a solution of 6 g. of7-chloro-2-methylamino-5- phenyl-3H-1,4-benzodiazepine 4-oxidehydrochloride in 25 m1. of pyridine, 2.7 g. of isovaleryl chloride wasadded. The mixture was left at room temperature for 16 hours and thenconcentrated in vacuo. The residue was dissolved in methylene chloride,washed with dilute ice cold hydrochloric acid, then sodium carbonatesolution and water. The organic layer was separated, dried andconcentrated in vacuo. The residue was crystallized from a mixture ofether and petroleum ether yielding colorless prisms of3-isovaleryloxy-7-chloro 2 methylamino-S-phenyl-ZH- 1,4-benzodiazepinemelting at 132-133 Analysis.Calcd. for C H ClN O C, 65.70; H, 5.78.Found: C, 66.50; H, 5.91.

Example 11 To a solution of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml. of dimethylformamide was added 5ml. of benzoyl chloride. The mixture was left at room temperature forthree days, then ice water was added and the reaction product extractedwith methylene chloride. The organic solution was separated, dried andconcentrated in vacuo. To the residual oil, ether was added and theprecipitated crystals of 3-benzoyloxy- 7-chloro 2methylamino-S-phenyl-SH-1,4-benzodiazepine were filtered off. Afterrecrystallization from acetone the product formed prisms melting at215-216".

The same product was obtained by benzoy'lation of 7- chloro 2methylamino-S-phenyl-BH-1,4-benzodiazepine 4-oxide in pyridine solution.

Example 12 To a solution of 10 millimols of 2-methylamino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine 4 oxide in 20 ml. ofdimethylformamide, 15 millimols of acetyl chloride were added whilestirring. The solution was permitted to stand for one hour at roomtemperature. At the end of this period, the solvent was distilled off atbelow 35 in vacuo. The residue was then refluxed with acetone, chilledand filtered to give 3-acetoxy-2-methylamino-S-phenyl 7trifluoromethyl-3H-1,4-benzodiazephine hydrochloride which upon tworecrystallizations from acetonitrile formed colorless needles meltingat206- 207.

Calc. for C H F N O HCI: C, 55.41; H, 4.16; N, 10.20. Found: C, 55.67;H, 4.36;N, 10.53.

700 mg. of 3-acetoxy-2-methylamino-5-phenyl-7-trifluoromethyl-3I-I-1,4-benzodiazepine hydrochloride was partitioned between chloroformand dilute sodium carbonate. The organic layer was washed with water,dried over sodium sulate, filtered and concentrated to dryness in vacuo.The residue was crystallized from a mixture of benzene and hexaneyielding 3-acetoxy-2-methylamino-5- phenyl-7-trifluoromethyl 3H-1,4benzodiazepine which crystallized as heavy colorless prisms; M.P.211-212.". Further recrystallization did not alter the melting point.

Analysis.-Calcd. for C19H1 F3N302i N, Found, N, 11.04.

The above-mentioned2-methylamino-5-phenyl-7-trifluoromethyl-SH-1,4-benzodiazepine 4-oxide,its preparation and intermediates therefor, are not a part of thisinvention, but such are disclosed hereinbelow in order that the presentdisclosure may be complete.

g. of sodium nitrite were added slowly with stirring to 460 ml. ofconcentrated sulfuric acid. After heating to 70, a clear solution wasobtained. This solution was cooled and 200 g. of2-chloro-S-trifluoromethylaniline were slowly added at a temperaturebetween 10 and 20.

The reaction mixture was stirred for one hour at 20 and then poured ontoa mixture of 200 g. of sodium chloride and 1.6 kg. of ice. Excess sodiumchloride was filtered off. A solution of 280 g. of zinc chloride in 300ml. of water was added to the filtrate whereupon a zinc chloride doublesalt of the corresponding diazonium compound precipitated. Afterstanding overnight at 0, the double salt was filtered off and washedwith a cold saturated salt solution.

To a solution of g. of sodium cyanide and 72 g. of cuprous cyanide in300 ml. of water were added with stirring and cooling with ice, 291 g.of the wet zinc chloride double salt. After the addition of 24 g. ofsodium carbonate, the mixture was first stirred for one hour at 20 andthen at 70 for an additional /2 hour. The reaction mixture was cooledand extracted with ether to obtain crude2-chloro-5-trifluoromethylbenzonitrile. The product was purified bysteam distillation and crystallization of the organic part of thedistillate from hexane to give the pure compound, M.P. 39-40.

To a solution of phenyl magnesium bromide, prepared from 9.5 g. ofmagnesium, 58.5 g. of bromobenzene and 500 ml. of anhydrous ether, wasadded with stirring a solution of 39 g. of2-chloro-5-trifiuoromethylbenzonitrile in 200 ml. of benzene. 400 ml. ofsolvent were distilled off and the reaction mixture was then refluxedfor 16 hours. The Grignard complex was decomposed with 40 g. of ammoniumchloride and 200 g. of ice. The mixture was then extracted with benzene.2-chloro-5-trifluoromethylbenzophenone imine hydrochloride wasprecipitated from the benzene solution by the addition of 40 ml. ofconcentrated hydrochloric acid. The product was filtered off, washedwith benzene and dried in vacuo, M.P. 248-251, and upon furtherpurification melted at 250-262.

60 g. of 2-chloro-5-trifiuoromethylbenzophenone imine hydrochloride wererefluxed overnight with a mixture of 300 ml. of toluene and 300 ml. of25% sulfuric acid while stirring. The toluene layer was separated,washed with water, dried, concentrated in vacuo and the residuecrystallized from hexane to yield pure2-chloro-5-trifluoromethylbenzophenone, M.P. 39-40 (corr.).

50 g. of 2-chloro-5-trifiuoromethylbenzophenone and 500 ml. ofconcentrated aqueous ammonia were reacted in a closed vessel for 10hours at in the presence of 10 g. of cuprous chloride catalyst. Thereaction product was extracted with ether. The ether extract wasconcentrated in vacuo, and the residue dissolved in hexane and purifiedby chromatography using a 10 fold amount of neutral alumina (Brockmannactivity state H). Elution with a hexane-ether mixture (1:1) andevaporation of the solvent gave 2 amino 5 trifluoromethylbenz/ophenonewhich was recrystallized from hexane to give yellow crys tals, M.P.81-82 (corr.).

13.3 g. of 2-amino-5-trifiuoromethylbenzophenone in 60 ml. of ethanolwere refluxed for 24 hours with 6 g. of hydroxylamine hydrochloride. Thereaction mixture was adjusted to about pH 6 by the addition of asolution of 12 g. of sodium acetate in 100 ml. of water. The mixture wasthen extracted wi.h ether to yield an oil which, after repeatedcrystallization from a mixture of ether and hexane, gave 2 amino 5trifiuoromethylbenzophenone oxime melting at 175l77, which upon furthercrystallization melted at 182-183 (corr.).

2.8 g. of the 2-amino-5-trifluoromethylbenzophenone oxime obtained abovewere dissolved in ml. of acetic acid and, after addition of 1.5 ml. ofchloroacetyl chloride, kept for one hour at then for two hours at 70.The mixture was diluted with ether and washed with water. The ethersolution was concentrated in vacuo and gave a solid residue which wascrystallized from methylene chloride-ether to yield pure, yellow2-chloromethyl- 4 phenyl 6 trifiuoromethylquinazoline 3-oxide, M.P.149l50.

500 mg. of 2-chloromethyl-4-phenyl-6-trifluoromethylquinazoline 3-oxidewere reacted for 5 hours at with' 10 ml. of a solution of methylamine inmethanol. The reaction mixture was diluted with water, then extractedwith ether. The ether solution was concentrated in vacuo and theresidual crude,7-trifiuoromethyl-Z-methylamino-5-phenyl-3H-1,4-benz0diazepine 4-oxide,was purified by crystallization from ether-hexane to yield colorlesscrystals melting at 257-25 8, which upon recrystallization melted at264265.

Example 13 To a solution of 100 mg. of 2-methylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 5 ml. of dimethylformamide,0.5 cc. of acetyl chloride was added. After stirring for one hour atroom temperature, the reaction mixture was concentrated to dryness invacuo. The residue was dissolved in acetone and precipitated withanhydrous ether to give 85 mg. of crude 3-acetoxy- 2-methylamino 7nitro-5-phenyl-3H-1,4-benzodiazepine hydrochloride. This was thenpartitioned between chloroform and dilute sodium hydroxide. The organiclayer was washed twice with water, dried over sodium sulfate, filtered,and concentrated to dryness in vacuo. The residue was crystallized froma mixture of benzene and hexane to give3-acetoxy-2-methylamino-7-nitro-5-phenyl-3H-1,4- benzodiazepine, M.P.210212, which crystallized as clusters of yellow rectangular plates.

The above mentioned 7-nitro-2-methylamino-5-phenyl- 3H-14-benzadiazepine4-oxide, its preparation and intermediates therefore, are not a part ofthis invention, but such are disclosed hereinbelow in order that thepresent disclosure may be complete.

A mixture of 72 g. of 2-amino-5-nitrobenzophenone, 34 g. ofhydroxylamine hydrochloride, 90 g. of powdered potassium hydroxide, 500cc. of alcohol and 25 cc. of water was refluxed on a steam bath withstirring for 15 minutes. It was then cooled to room temperature andpoured into a solution of 160 cc. of concentrated hydrogen chloride in1000 cc. of water. The suspension of the precipitated crude product wascooled in ice and then filtered off, washed acid-free with ice water,and sucked dry, and crystallized from ethanol in needles, giving 2-amino-S-nitrobenzophenone oxime, M.P.=203205.

To a suspension of 10 g. of Z-aminoJ-nitrobenzophenone oxime in 100 cc.of acetic acid, warmed to -60", 6 cc. of chloracetyl chloride was addedin small portions, with stirring. The resulting brown solution wasstirred at 50-60 for 3 hours and then allowed to stand at roomtemperature overnight. The reaction mixture was then saturated withhydrogen chloride and concentrated in vacuo. The residue was dissolvedin 200 cc. of warm methylene chloride and was then cooled to 0. 50 g. ofcrushed ice was added to the reaction mixture, then 30 cc. of 1 N sodiumhydroxide dropwise until a pH of 8-9 was reached. The mixture wastransferred to a separatory funnel and 150 cc water were added. Theorganic phase was separated and dried over sodium sulfate. The methylenechloride solution was treated with activated charcoal, filtered, andevaporated to dryness in vacuo to give a yellow crystalline residue. Thecrude product was purified by refluxing in a mixture of 200 cc. ofacetone and cc. of methylene chloride with 15 g. of activated charcoal.2-chloro-methyl-4-phenyl-6-nitroquinazoline 3- oxide crystallized inyellow prisms on cooling of the filtered mixture. M.P.=205207.

6.0 g. of 2-chloromethyl-4-phenyl-6-nitroquinazoline 3- oxide was addedin portions to cc. of a 25 percent solution of methylamine in methanolat 5 with cooling and stirring. After a few minutes, a yellowcrystalline substance started to separate. The reaction mixture wasstirred at room temperature for 24 hours then allowed to stand foranother 24 hours. The yellow product was filtered off, washed with alittle methanol, sucked dry, and crystallized in needles fromether-methanol giving 7-nitro- 2 methylamino 5 phenyl 3H 1,4benzodiazepine 4-oxide, which melted at 260261 (dec.).

Example 14 To a solution of 6.9 g. of 3-acetoxy-2-methylamino-5- phenyl7 trifluoromethyl 3H 1,4 benzodiazepine hydrochloride in 150 ml. ofethanol at 50, 25 ml. of 2 N sodium hydroxide was added and the mixturestirred for 20 minutes at 40-50. After cooling and dilution with 150 ml.of water, 16.7 ml. of l N hydrochloric acid was added. The solution wasthen extracted with chloroform. The chloroform layer was washed withwater, dried over sodium sulfate, filtered and concentrated to drynessin vacuo. On warming the residue with hexane, the product 2-meth ylamino5 phenyl 7 trifluoromethyl 3H 1,4 benzodiazepin-3-ol crystallized; M.P.177178 (dec.). Recrystallization from a mixture of benzene and hexanegave clusters of colorless rods of unchanged melting point.

Example 15 A solution of 2.0 g. of 3 acetoxy 2 methylamino 7-nitro-5-phenyl-3H-1,4-benzodiazepine in 100 ml. of ethanol containing 5ml. of 22 percent hydrogen chloride in ethanol was heated to reflux for5 minutes. After concentration to a small volume in vacuo, the residuewas partitioned between chloroform and dilute sodium carbonate. Theorganic layer was washed with water, dried over sodium sulfate, filteredand the solvent distilled olf in vacuo. The residue was recrystallizedfrom a mixture of acetone and hexane to give yellow prisms of3-ethoxy-2- methylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine.Recrystallization from a mixture of tetrahydrofuran and hexane gave apurified product melting at 222-223.

Example 16 To a solution of 2.3 g. of 7-chloro-2-methylamino-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine 4-oxide in 25 ml. ofdimethylformamide at room temperature, 1 ml. of acetyl chloride wasadded. The temperature rose about 6. After stirring for 1 hour, thesolvent was distilled off in vacuo and the residue partitioned betweenchloroform and dilute sodium carbonate. The chloroform layer was washedwith water and dried over sodium sulfate. The residue obtained afterfiltration and distillation of solvent was crystallized fromacetonitrile to give 3-acetoxy-7- chloro 2 methylamino 5 (4methoxyphenyl) 3H- 1,4benzodiazcpine which upon recrystallization from amixture of tetrahydrofuran and hexane gave a pure product melting at202-203".

Example 17 Ammonia gas was passed into a stirred suspension of 3.75 g.of the acetyl ester of 3-acetoxy-2-methylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine in 250 ml. of ethanol for 2 hours.After 15 minutes a clear solution had formed. The reaction mixture waskept overnight at room temperature and the solvent was then distilled invacuo. The residue was dissolved in 100 m1. of acetone and decolorizedby heating with about 2 guns. of activated charcoal (Norite A). The paleyellow solution was concentrated to dryness in vacuo and the residuecrystallized from a mixture of methylene chloride and hexane to givecrude 2 methylamino 7 nitro phenyl 3H 1,4- benzodiazepin-3-ol which uponrecrystallization from acetonitrile gave yellow plates melting at163-I64.

We claim:

1. A compound selected from the group consisting of compounds of theformula and their pharma-ceutically acceptable salts,

wherein R is selected from the group consisting of hydrogen and loweralkanoyl; R is selected from the group consisting of hydrogen and loweralkyl; R is selected from the group consisting of hydrogen, lower alkyl,lower alkanoyl, and benzoyl; R is selected from the group consisting ofhydrogen, halogen, lower alkoxy and trifiuoromethyl; R is selected fromthe group consisting of hydrogen, halogen, trifluoromethyl, nitro, loweralkylthio and lower alkyl. 2. 7-halo-2-lower alkylamino-5-phenyl-3-loweralkanoyloxy-3H-1,4-benzodiazepine.

3. 7 halo 2 lower alkylamino 3 hydroxy 5- phenyl-3H.-l,4-benzodiazepine.

4. 7 trifluoromethyl 2 lower al-kyla rnino 5 phenyl- 3-loweraIkanoyIOXy-BH-1,4-benzodiazepine.

5. 7 chloro 2 methylamino 5 phenyl 3 hydroxy-3H-l,4-benzodiazepine.

6. 7 trifiuoromethyl 2 methylamino 5 phenyl-3-hydroxy-3H-1,4-benzodiazepine.

7. A compound selected from the group consisting of a compound of theformula R CHOR:

and the pharmaceutically acceptable salts thereof wherein R is selectedfrom the group consisting of hydrogen and lower alkanoyl; R is selectedfrom the group consisting of hydrogen and lower alkyl; R, is selectedfrom the group consisting, of hydrogen, lower alkanoyl, and benzoyl; Ris selected from the group consisting of hydrogen, chlorine, fluorine,methoxy, and trifiuoromethyl, and R is selected from the groupconsisting of hydrogen, chlorine, bromine, trifluoromethyl, and nitro.

8. A method which comprises reacting a compound of the formula CHO Rawherein R is selected from the group consisting of hydrogen and loweralkanoyl, R is selected from the group consisting of lower alkanoyl andbenzoyl and R R and R have the same meaning as above.

References Cited UNITED STATES PATENTS 8/1962 Reeder et al. 260-*239OTHER REFERENCES Klingsberg: Pyridine and Derivatives, Part Two (NewYork, 1961), pp. 125-128.

Cnlvenor: Reviews Pure and Applied Chem, vol. 3, pp. -109 (1953).

ALTON D. ROLLINS, Primary Examiner.

JOHN D. RANDOLPH, NICHOLAS S. RIZZO, ALEX MAZEL, Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,374,225 March 19 1968 Earl Reeder et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 10, lines 33 to 43, the formula should appear as shown below: I R

/'R 2 CHOR 4 Signed and sealed this 23rd day of September 1969.

(SEAL) Attest:

WILLIAM E. SCHUYLER, IR.

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA
 8. A METHOD WHICH COMPRISES REACTING A COMPOUND OF THE FORMULA